System layout for an automated system for sample preparation and analysis

ABSTRACT

A sample preparation and analysis system. The system includes a housing with a sample preparation station and a sample analysis station positioned within the housing. The sample analysis station is spaced away from the sample preparation station. A transport assembly is configured to move at least one sample within the housing and between the sample preparation station and the sample analysis station.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a divisional of co-pending U.S. patent applicationSer. No. 13/882,399, filed Jul. 17, 2013, which is a submission under 35U.S.C. §371 of International Application No. PCT/US2011/058323, filedOct. 28, 2011, which claims the filing benefit of U.S. ProvisionalApplication Ser. No. 61/408,180, filed Oct. 29, 2010, the disclosures ofwhich are hereby expressly incorporated by reference herein in theirentireties.

FIELD OF THE INVENTION

The present invention relates generally to the field of samplepreparation and analysis and, more particularly, to systems and layoutsfor arranging sample preparation and analysis instrumentations.

BACKGROUND OF THE INVENTION

Liquid chromatography mass spectrometry (“LCMS”) is a powerful analytedetection and measurement technique that has become the preferred methodof detecting small molecule, amino acid, protein, peptide, nucleic acid,lipid, and carbohydrate analytes to a high accuracy for diagnosticpurposes. However, the instrumentation required for LCMS is technicallycomplex and not well suited to the typical hospital clinical lab ormedical lab technician. These clinical labs have not adopted LCMSdiagnostics and, instead, generally use alternative diagnostictechniques, including automated immunoassay. Alternatively, the clinicallabs may send the samples out to a central laboratory for analysis.

Therefore, there is a need for sample preparation and sample analysissystems that are less complex to configure and use for preparing samplesand conducting a variety of different analyte assays, without requiringthe expertise of LCMS technologists, or the massive scale of a referencelaboratory. There is yet also a need for a sample preparation and sampleanalysis systems that improve the efficiency of the time to result for avariety of different analyte assays.

SUMMARY OF THE INVENTION

The present invention overcomes the foregoing problems and othershortcomings, drawbacks, and challenges of conventional samplepreparation and sample analysis systems. While the invention will bedescribed in connection with certain embodiments, it will be understoodthat the invention is not limited to these embodiments. To the contrary,this invention includes all alternatives, modifications, and equivalentsas may be included within the spirit and scope of the present invention.

In accordance with one embodiment of the present invention, a samplepreparation and analysis system includes a housing. A sample preparationstation and a sample analysis station are positioned within the housingand with the sample analysis station is spaced away from the samplepreparation station. A transport assembly is configured to move at leastone sample within the housing and between the sample preparation stationand the sample analysis station.

According to another embodiment of the present invention, an automatedbiological specimen preparation and mass spectrometry analysis systemincludes a sample preparation station and a sample analysis station. Thesample preparation station is configured to prepare samples that aretaken from a plurality of biological specimens. The sample analysisstation includes a mass spectrometer that is configured to quantify oneor more analytes in the prepared samples. The sample preparation and thesample analysis stations are contained within a housing such that themass spectrometer is lower than the sample analysis station.

According to yet another embodiment of the present invention, anautomated biological specimen preparation and analysis system includes asample preparation station and a sample analysis station. The samplepreparation station is configured to prepare samples that are taken froma plurality of biological specimens and includes a first serviceablecomponent, which may include a specimen rack and/or a reagent rack. Thesample analysis station configured to quantify one or more analytes inthe prepared samples and including a second serviceable component, whichmay include a liquid chromatography column and/or a liquidchromatography mobile phase container. A third serviceable componentincludes a fluid container and/or a waste container. The samplepreparation station, the sample analysis station, and the thirdserviceable component are contained within a housing such that thefirst, second, and third serviceable components are positioned closer toa front face of the housing than to a back face of the housing.

Still another embodiment of the present invention is directed to anautomated biological specimen preparation and analysis system andincludes a sample preparation station and a sample analysis station. Thesample preparation station is configured to prepare samples that aretaken from a plurality of biological specimens. The sample analysisstation is configured to quantify one or more analytes in the preparedsamples. A user interface is configured to receive and/or conveyinformation to a user. A housing contains the sample preparation andsample analysis stations. The user interface s mounted to an exteriorportion of the housing and positioned between a left-hand sidewall and aright-hand sidewall of the housing.

According to another embodiment of the present invention, an automatedbiological specimen preparation and analysis system includes samplepreparation and sample analysis stations positioned within a housing.The sample preparation station is configured to prepare samples takenfrom patient specimen. The samples are prepared in accordance with anassay selected from a database containing a plurality of unique assays.The sample analysis station includes an analyzer that is dynamicallyreconfigurable according to the selected assay. Once dynamicallyreconfigured, the analyzer analyzes the prepared sample. A transportmechanism is configured to transport the prepared sample within thehousing and from the sample preparation station to the sample analysisstation.

The above and other objects and advantages of the present inventionshall be made apparent from the accompanying drawings and thedescriptions thereof.

BRIEF DESCRIPTION OF THE FIGURES

The accompanying drawings, which are incorporated in and constitute apart of this specification, illustrate embodiments of the invention and,together with the general description given above and the detaileddescription of the embodiments given below, serve to explain theprinciples of the present invention. In the figures, corresponding orlike numbers or characters indicate corresponding or like structures.

FIG. 1A is a perspective view of an automated sample preparation andanalysis system in accordance with one embodiment of the presentinvention.

FIG. 1B is a perspective view of an automated sample preparation andanalysis system in accordance with another embodiment of the presentinvention.

FIG. 2A is a top view of the automated sample preparation and analysissystem of FIG. 1A.

FIG. 2B is a top view of the automated sample preparation and analysissystem of FIG. 1B.

FIG. 3A is a side elevational view of the automated sample preparationand analysis system of FIG. 1A with the front cover removed.

FIG. 3B is a side elevational view of the automated sample preparationand analysis system of FIG. 1B with the front cover removed.

FIG. 4 is a schematic view of a sample preparation station and atransport assembly of the automated sample preparation and analysissystem of FIG. 1A in accordance with one embodiment of the presentinvention.

FIG. 5 is a schematic view of a sample preparation station and a sampleanalysis station of the automated sample preparation and analysis systemof FIG. 1A in accordance with one embodiment of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

FIG. 1A is a perspective illustration of an automated sample preparationand analysis system 10 according to one exemplary embodiment of thepresent invention (referred to hereinafter as “system” 10). The system10 is designed to automatically prepare a sample from a specimen foranalysis and to analyze the prepared sample according to a predeterminedanalyte assay selected from a variety of different or unique analyteassays. As will be described in greater detail below, the exemplarysystem 10 is particularly designed to perform two distinct laboratoryfunctions, i.e., sample preparation and sample analysis, in combinationin an automated system.

In one embodiment, the system 10 includes a sample preparation station12 for preparing various samples and a sample analysis station 14, whichincludes a suitable analyzer, such as a liquid chromatography massspectrometer (“LCMS”), a gas chromatography mass spectrometer (“GCMS”),a surface desorption/ionizer directly coupled to a mass spectrometer; aliquid chromatography ultra-violet spectrometer (“LC/UV-VIS”), or afluorescence spectrometer, for example, for analyzing the preparedsamples according to selected analyte assays. The sample preparationstation 12 and the sample analysis station 14 are interconnected in anautomated manner as will be described in detail below and may, in fact,be enclosed within a unitary cover 16.

The unitary cover 16 is designed to be compartmental, permittingrelative isolation of each station 12, 14. For example, according to theexemplary system depicted in FIG. 1A, the unitary cover 16 is formed ofmetal partitions and includes separate compartments for each of thesample preparation station 12 and the sample analysis station 14, forexample, any associated liquid chromatography pumps, a centrifuge rotor,one or more power units, controllers 21, 23, mobile phase containers128, and waste containers 70.

FIG. 1B, like FIG. 1A is a perspective illustration of an automatedsample preparation and analysis system 10′ and were similar numbers withprimes refer to similar features.

Referring still to FIGS. 1A and 1B and now also to FIGS. 2A and 2B, thesample preparation station 12 of the system 10 may include a samplepreparation station 20 and a sample preparation controller 21 thatcontrols selected functions or operations of the sample preparationstation 20. The sample preparation station 20 is configured to receiveone or more specimens, to sample the specimens to prepare the samplesfor analysis according to a variety of preselected analyte assays, andto transport the prepared samples for analysis to the sample analysisstation 14. In some embodiments, the sample preparation station 20 isconfigured to prepare the sample such that the prepared sample ischemically compatible with the sample analysis station 14 according tothe selected analyte assay to be performed by the sample analysisstation 14.

The sample analysis station 14, in like manner, includes a sampleanalysis station 24 and a sample analysis controller 23 that controlsselected functions or operations of the sample analysis station 24. Thesample analysis station 24 is configured to receive the prepared samplefrom the sample preparation station 20 via a transport mechanismdescribed in greater detail below. The sample analysis station 24 thenanalyzes the prepared sample according to a selected analyte assay toobtain a result for that sample. The sample result may be transmitted tothe sample preparation controller 21, which may validate the results.

While not specifically shown, a general controller may be used tocontrol the sample preparation controller 21 and the sample analysiscontroller 23 or, alternatively, the sample analysis controller 23 maybe made a slave to the master sample preparation controller 21, or viceversa. Further, while the designation of the sample preparationcontroller 21 and the sample analysis controller 23 as provided hereinseems to indicate that the sample preparation station 20 and the sampleanalysis station 24 comprise two opposing sides of the system 10, thestations 12, 14 may encompass the same area or footprint. Indeed, inaccordance with the present invention, in some embodiments the samplepreparation station 20 and the sample analysis station 24 need not beencompassed within the same housing or unit.

The sample preparation station 20 includes a specimen dock 26 having oneor more specimen racks 28. Each specimen rack 28 includes one or morespecimen rack positions capable of holding a specimen container 30. Thespecimen containers 30 are configured to contain the acquired biologicalor environmental specimens, which may be any specimen containing orsuspected of containing an analyte of interest. These patient specimensor environmental samples may be analyzed for one or more analytes, whichmay include, but are not limited to, drugs, pro-drugs, metabolites ofdrugs, metabolites of normal biochemical activity, peptides, proteins,antibiotics, metabolites of antibiotics, toxins, microorganisms(including bacteria, fungi, and parasites), and infectious agents(including viruses and prions). Further, any of the foregoing samples,alone or in combination, may be suspended in an appropriate media, forexample, within a blood culture or a screening booth.

The specimen container 30, itself, may include any suitable labware,such as a vessel, a vial, a test tube, or any other suitable containerknown in the art. One or more of the specimen racks 28 may bedesignated, or otherwise labeled (e.g., by placement of the rack 28within the sample preparation station 20 or with a barcode or an RFIDantenna), as priority racks 28 a, or STAT, for introducing specimencontainers 30 having urgent specimens. The sample preparation station 20further includes a reagent station 36 containing multiple reagent racks38. Each reagent rack 38 includes one or more reagent rack positionscapable of holding one or more reagent containers 40 that containsolvents and/or reagents, some of which may be comprised of a volatileliquid.

A touch screen display 32 or other similar user interface is positionedon the upper half of the system 10 and in a central position of thehousing 16. Placing the touch screen display 32 within the footprint ofthe system 10 rather than as a stand-alone computer or as an appendageattached to the side of the system 10 reduces the overall footprint ofthe system 10 and frees floor space in the laboratory environment. Giventhe overall length of the system 10, placement of the touch screendisplay 32 centrally reduces the maximum distance between the touchscreen display 32 and each of the sample preparation station 12 and thesample analysis station 14. Reducing this distance, as much as possible,is advantageous for the user who needs to review messages provided onthe touch screen display 32, for example, specimen addition or reagentreplenishment instructions, while nearly simultaneously attending to theuser serviceable components of the system 10, for example, addingspecimen racks or new reagent containers to the system 10. Additionally,the touch screen display 32 is mounted in a manner to make the interfaceadjustable, both for height as well as for angle of incline, to optimizeits position for each individual user.

A patient sample (referred to hereinafter as “sample”), or a portion ofa particular specimen contained within a specimen container 30 istransferred to an open-top sample vessel 44 (also known as a reactionvessel, but referred to hereinafter as “vessel” 44) to be prepared foranalysis. The vessels 44 may be stored within, and introduced from, astorage station (not shown) of the sample preparation station 20. Withinthe storage station, the vessels 44 may reside in plates (not shown) orother appropriate mass storage containers. As various ones of thevessels 44 are transferred and periodically leaving empty plates, theplates may be discarded through a waste chute 48 from the samplepreparation station 20.

When a specimen is sampled, one or more vessels 44 are transferred to asampling station 46 from the storage station by way of a transportassembly 50 (FIG. 4). The transport assembly 50 (FIG. 4) may include arobot assembly operating on one or more tracks 52 and configured to movein at least one of an x-y direction, an x-y-z direction, or a rotarydirection. An exemplary track system and associated transport bases aredescribed in detail in co-owned U.S. Pat. No. 6,520,313, entitled“Arrangement and Method for Handling Test Tubes in a Laboratory,” naminginventors Kaarakainen, Korhonen, Makela, and which is herebyincorporated by reference in its entirety herein.

The sampling station 46 may include a rotatable table 94 having a vesselcap opening and closing device 96 for opening and closing a hinged lidof the vessel, if present. One having ordinary skill in the art willappreciate that alternative embodiments of a transport mechanism totransport a portion of a particular specimen contained within a specimencontainer 30 to the vessel 44 may be used without departing from thescope of embodiments of the invention.

While not shown, the transport assembly 50 may further include agripper, or other like device, to capture and release the vessel 44 or atransport handle 54 associated with a vessel rack 56, if used, tosimultaneously transport two or more vessels 44 within the system 10.

In another embodiment, not shown, the transport assembly 50 may includea robot assembly configured to move in at least one of an x-y direction,an x-y-z direction, or a rotary direction and which may include anautomated liquid handler. According to this embodiment, the automatedliquid handler may aspirate and dispense a volume of a liquid betweentwo or more vessels 44 within the system 10 to transport the liquidbetween two or more stations within the system 10.

In still other embodiments, the transport assembly 50 may furtherinclude carousels, i.e., a circular revolving disc, or autosamplershaving multiple vessel positions therein to provide transport functionand allow for a temporary, intermediate vessel storage function.

The transport assembly 50 may further comprise a sample pipette assembly58 (FIG. 4) having a pipette shaft 60 (FIG. 4) that is movable, forexample via a robotic device, in one or more of the x-y-z directions andbetween two or more of the specimen dock 26, the reagent station 36, andthe sampling station 46.

The sample pipette assembly 58 may aspirate an aliquot of the specimenfrom the specimen container 30 from within the specimen dock 26 anddispense the aliquot of the specimen into the vessel 44 within thesampling station 46. Additionally, or alternatively, the sample pipetteassembly 58 may aspirate an aliquot of a desired reagent from one of thereagent containers 40 within the reagent station 36 and dispense thealiquot of the desired reagent into the vessel 44 within the samplingstation 46, which may or may not previously include the sample, i.e.,the aliquot of the specimen.

According to still another embodiment, the sample is selected from aculture plate using a commercially-available colony picker instrument,for example, the PICKOLO (Tecan Group, Ltd., Männedorf, Switzerland) orthe QPIX (Genetix, now part of Molecular Devices, San Jose, Calif.). Thecolony picker is capable of collecting an aliquot of the specimen 23from a colony, optionally, a pre-selected or pre-designated colony, on aculture plate and depositing the sample into the vessel 44. Thecolony-containing vessel may then be mixed, as described above, to lysethe cells and denature the proteins in order to stabilize the sample forlater microbial analysis.

The sample within the vessel 44 is transferred via the transportassembly 50 from the sampling station 46 to a secondary processingstation 72. The secondary processing station 72 includes, for example,one or more of a mixing station 74, an incubation station, and a matrixinterference removal station (shown specifically herein as a centrifuge76).

The matrix interference removal station, if included within thesecondary processing station 72, may be incorporated in either of anon-line or off-line configuration (e.g., the on-line configuration beinga configuration in which the sample moves between one or more stationsof the sample preparation station 20 through fluidic connections withoutbeing contained in a vessel 44, the off-line configuration being aconfiguration in which the sample is transported within a vessel 44between stations of the sample preparation station 20). In embodimentsthat include an on-line matrix interference removal station, theanalyte-containing prepared sample may flow directly from the matrixinterference removal station to the next station, such as throughtubing. This second station may include, for example, a second matrixinterference removal station (not shown). In embodiments that include anoff-line matrix interference removal station, the analyte-containingprepared sample is collected from the matrix interference removalstation and placed into a vessel 58 if not already contained in a vessel44.

The matrix interference removal station is operable to separate one ormore of residual proteins, phospholipids, salts, metabolites,carbohydrates, nucleic acids, and/or other substances that may otherwiseinterfere with subsequent processing or analysis of the desired analytesand prior to transferring the now prepared sample to the sample analysisstation 24. In some embodiments, the matrix interference removal stationseparates contaminants from the analyte-containing prepared sample, ormore simply, the “prepared sample” (for example, by separatingprecipitated solids from a resulting supernatant liquid, wherein thesupernatant liquid forms the prepared sample). The matrix interferenceremoval station may include, for example, one or more of a phaseseparation station (not shown), a centrifuge (illustrated as referencenumber 76 in FIG. 2A and reference number 76′ in FIG. 2B), a sonicator(not shown), a heating station (not shown), a flash freeze station (notshown), an affinity purification station (not shown), or a filtrationstation (not shown).

In still other embodiments, the matrix interference removal station mayinclude an affinity extraction or purification station, for example, animmunoaffinity extraction or purification system. An exemplaryimmunoaffinity system may use a Mass Spectrometry Immunoassay (“MSIA”)antibody enriched substrate, such as the commercially-available MSIAsubstrate from Intrinsic Bioprobes Inc. (Tempe, Ariz.) and that isdescribed in U.S. Pat. No. 6,783,672, the disclosure of which isincorporated herein in its entirety. Alternatively still, the matrixinterference removal station may, in yet other embodiments, includeadditional techniques known in the art of chemical separation, such asliquid-liquid extraction, solid phase supported liquid extraction,random access media column extraction, monolithic column extraction,dialysis extraction, dispersive solid phase extraction, solid phasemicro-extraction, immunoaffinity extraction, and size exclusion usingmembrane filters with gravity, vacuum, or centrifugation. Many of thesetechniques may be practiced off-line or on-line, as appropriate, iffluid connections are created between subsequent steps of the method.Additionally, many of these techniques may be practiced in a variety offormats including, for example, using a column or cartridge format,using a pipette tip format, using a magnetic bead format, or using aplate or chip format.

Embodiments of the system 10 that include a phase separation componentmay include an on- or off-line solid phase extraction station (notshown) having a vacuum and/or positive pressure source (not shown) toassist in moving the sample through a solid phase extraction matrix. Thesolid phase extraction matrix, in turn, may include one or more suitableporous stationary phase material layers. According to one embodiment,the solid phase extraction matrix (not shown) further includes one ormore filters arranged on one or both sides of the porous stationaryphase material. The solid phase extraction matrix may be arranged, forexample, within a column, cartridge, a pipette tip, or in a plate orchip format.

In still yet another embodiment, the matrix interference removal stationmay include two or more matrix interference removal methods in series.According to this embodiment, the first matrix interference removalstation, for example a phase separation station, removes precipitatedproteins while the second matrix interference removal station, forexample a solid phase extraction station, removes additional residualproteins, phospholipids, and salts from the sample prior to analysis.Additional examples of combinations of matrix interference removaltechniques include, but are not limited to, solid phase extractionfollowed by liquid-liquid extraction, phase separation followed by sizeexclusion affinity liquid chromatography, solid phase extractionfollowed by size exclusion affinity liquid chromatography, andimmunoaffinity extraction prior to or following any of theaforementioned methods.

After the sample has passed through the secondary processing station 72,the prepared sample is transported via the transport assembly 50 to ananalysis staging station 78. The analysis staging station 78 includestwo or more vessel positions 82 (FIG. 2A) or two or more vessel rackpositions 82′ (FIG. 2B) for accepting vessels 44 or vessel racks 56,respectively. Each vessel position 82 may be stationary within theanalysis staging station 78 such that once an individual vessel 44 isplaced within a vessel position 82 of the analysis staging station 78,its position does not change but for transfer by the transport assembly50.

When a particular prepared sample is selected for analysis, the vessel44 containing the prepared sample is transferred via the transportassembly 50 from the analysis staging station 78 to an injector station84. The injector station 84 may include an injector pipette assembly 86(FIG. 4) to transfer an aliquot of the prepared sample from the vessel44 to the sample analysis station 24. The injector pipette assembly 84includes a pipette shaft 88 (FIG. 4) that may be constructed in a mannerthat is similar to the sample pipette assembly 58 that was described indetail above.

The injector station 84 may include a rotatable table 94 having astructure that is similar to the sampling station 46 and may include avessel cap opening and closing device 96 for opening and closing ahinged lid, if present, and as shown in FIG. 2B.

As described in detail above, a sample of a specimen is prepared at thesample preparation station 20 before that prepared sample is moved tothe sample analysis station 24. As such, at least some of the movableportions of the sample preparation station 20, including the samplingstation 46, the transport assembly 50, the rotatable tables 94, and theinjector pipette assembly 84, acting individually or in concert, maycomprise a transport mechanism to transport the prepared sample from thesample preparation station 12 to the sample analysis station 14. Onehaving ordinary skill in the art will appreciate that alternativeembodiments of a transport mechanism to transport a prepared sample froma sample preparation station 12 to a sample analysis station 14 may beused without departing from the scope of embodiments of the invention.In the exemplary embodiment, the transport mechanism may comprise theinjector pipette assembly 84, which removes an aliquot of the preparedsample for dispensing to the sample analysis station 24.

Turning now to the details of the sample analysis station 24, and inparticular to FIGS. 2A-3B and 5, one embodiment of the sample analysisstation 24 may be an LCMS system having a liquid chromatography station102 and a mass spectrometer station 104. The liquid chromatographystation 102 (referred to hereinafter as “LC station” 102) may includeone, two, or more injection ports 106, 108 for accepting the aliquot ofthe prepared sample from the injector pipette assembly 86 for analysis.The injection ports 106, 108 may be connected on-line to one or morechromatography columns (e.g., a preparatory column 110 or an analyticalcolumn 112) for separation of the prepared sample into analytes ofinterest eluting at one or more elution times and a plurality ofancillary or waste eluents. As shown in the illustrative embodiments,the LC station 102 includes two separation channels, i.e., LC channels110, 112 (a third LC channel 118 shown in phantom). Each LC channel 110,112, 118 includes one preparatory column 114 and one analytical column116, arranged in series. The preparatory column 114, according to someembodiments, may be a size exclusion affinity liquid chromatographycolumn used for, in essence, matrix interference removal. The analyticalcolumn 116 may be a reversed-phase LC column for analyte isolation.

In other embodiments, the preparatory column 114 may be a conventionalsize exclusion column or any other liquid chromatography column that maybe utilized as a matrix interference removal device.

Each of the two LC channels 114, 116 is associated upstream with arespective injector port 106, 108 and associated downstream with asingle mass spectrometer 120 of the mass spectrometer station 104 in amanner that enables multiplexing or staggered sample introduction intothe mass spectrometer 120 as described in detail below.

Referring still to FIG. 5, each LC channel 114, 116 may be furtherassociated with at least one pump 124 and at least one valve 126 tocontrol the flow of the mobile phases and the prepared sample throughthe sample analysis station 24.

The mobile phase is pumped to an injection valve 126 having a rotatablecenter 134 and six ports fluidically coupled to one injection port 106,108 one or more of the mobile phase supplies 128, 128′ (FIGS. 3A, 3B),the waste container 70, 70′ (FIGS. 3A, 3B), the columns 110, 112, and afluid loop 132 connecting Port-2 to Port-5.

The injected, prepared sample moves through the columns 110, 112 in aknown manner such that at least one of the analytes of interest willelute off the columns at a retention time that differs from theretention time of other analytes of interest and/or the matrixcomponents, i.e., eluents. The eluents and analytes from both of thefirst and second LC channels 114, 116 are directed into a valve 139(which may also include an auxiliary port 138) where the eluents aredirected into the waste container 70, 70′ (FIGS. 3A, 3B) while theanalytes are directed to an ionization source 142 of the massspectrometer station 112. Alternative methods of sample introduction mayinclude, but are not limited to, on-line methods (such as, flowinjection analysis, direct infusion, and injection loops) and off-linemethods (such as, solid phase extraction, blood spot surface coatings,matrix-assisted laser desorption/ionization (“MALDI”) plate coatings, orcoatings on general surfaces), may also be used to introduce the sampleto the mass spectrometer 120.

As shown in FIG. 5, an atmospheric pressure ionization (eitherelectrospray ionization (“ESI”) or atmospheric pressure chemicalionization (“APCI”)) device (referred to generally herein as “nebulizingionizer”) is used for ionizing the analytes received by the ionizationsource 140. In that regard, the nebulizing ionizer includes a capillary,probe, or needle (referred hereinafter as “needle” 142) having a solventconduit therein (not shown) and surrounded by a gas conduit therein (notshown). An outlet of the gas conduit is positioned about 0.1 mm to about0.2 mm proximally to an outlet of the solvent conduit. In ESI operationa voltage generator 144 is electrically coupled to the needle 142 and isoperable to create a high voltage difference between the needle 142 andthe counter-electrode that is either at the mass spectrometer 120.

In use, a solvent is supplied to the solvent conduit at a rate rangingfrom about 400 μL/min to about 2000 μL/min; however, one of ordinaryskill in the art will readily appreciate that the solvent supply varieswith the particular ionization source selected. The particular solventused is dependent on the chemical nature of the analyte in study, andthe methodology for selection of an appropriate solvent is well known tothose of ordinary skill in the art. A gas, typically an inert gas suchas N2, is supplied to the gas conduit at pressures ranging from about 0bar to about 7 bar. The voltage generator 144 is activated and providesa voltage potential, typically ranging from about −5 kV to about 5 kV,to the solvent within the needle 142.

It would be readily appreciated that other ionization techniques areknown and may be implemented as necessary or desired. For instance,ionization sources 140 suitable for ionization of liquid samples mayinclude, for example, heated electrospray ionization (“HESI”), nanosprayionization (“NSI”), thermospray, sonic spray, atmospheric pressurephotoionization (“APPI”), laser diode thermal desorption (“LDTD”),atmospheric sampling glow discharge ionization source (“ASGDI”),paperspray ionization techniques capable of extracting a specimen from adried bloodspot, and inductively-coupled plasma (“ICP”). Ionizationsources 140 that are suitable for ionization of gas samples may include,for example, chemical ionization (“CI”), electron impact (“EI”),resonance enhanced multi-photon ionization (“REMPI”), resonancemulti-photon detachment (“RMPD”), glow discharge, and spark ionization.Furthermore, the ionization sources 140 for gas samples may be adaptedfor use with liquid samples. Ionization sources 140 that are suitablefor desorbtion and ionization of a sample from a surface include, forexample, MALDI, surface-assisted laser desorption/ionization (“SALDI”),surface-enhanced laser desorption/ionization (“SELDI”), desorptionelectrospray ionization (“DESI”), direct analysis in real time (“DART”),discontinuous atmospheric pressure interface (“DAPI”), laser diodethermal desorption (“LDTD”), and field desorption. This listing ofpossible ionization sources 140 is not exhaustive and may include otherionization sources and/or permutations as would be readily understood bythose of ordinary skill in the art of mass spectroscopy and analyticalchemistry.

A skimmer 147, positioned distal to a corona discharge electrode 145,acts in conjunction with an auxiliary gas (not shown, but directedbetween the outlets and the skimmer 147) to contain and/or focus the gasphase ions into a vacuum chamber of the mass spectrometer 120. Theauxiliary gas may be supplied at rates that range generally from about 0L/min to about 15 L/min.

Referring still to FIG. 5, the illustrative example of the massspectrometer 120 includes an interface 146 with the ionization source140, a mass filter 148, and an ion detector 150. The regions containingthe mass filter 148 and the ion detector 150 are maintained undervacuum. This interface 146 includes an orifice 152 of a skimmer cone 154that provides an opening into a higher vacuum chamber containing themass filter 148 while maintaining vacuum pressures.

In the illustrated example, the mass filter 148 is shown to be aconventional quadrupole operating as a mass filter; however, thoseskilled in the art will understand the determination by which theappropriate mass filter modality for a given assay is selected. In fact,other mass spectrometer embodiments may include, for example, a singlequadrupole modalities, time-of-flight (“TOF”) or exactive modalities,ion trap (“OT”) modalities, hybrid modalities, such as Q-TOF, TOF-TOF,Q-Exactive, LTQ-orbitrap, and LTQ-FT, or a mass spectrometer modifiedfor proton transfer.

Still other modalities are available, and may include, for example, ioncyclotron resonance (“ICR”) or magnetic sector-based analyzers. Whilethese modalities offer high resolution and specificity, each is alsovery expensive. Furthermore, other detectors/analyzers may be used with,or in place of the mass spectrometer. For example, these detectors mayinclude, for example, electrochemical devices, nuclear magneticresonance (“NMR”), absorbance, fluorescence, refractive index, pH,and/or conductivity.

In some embodiments, the resolution of the MS technique may be enhancedby employing “tandem mass spectrometry” or “MS/MS” for example via useof a triple quadrupole mass spectrometer.

It would be readily appreciated that by incorporating the variouscomponents of the sample preparation station 12 and the sample analysisstation 14 into a single system 10 may create certain contaminationrisks not otherwise observed in off-line systems. Therefore, the variouscomponents of these stations 12, 14 may be compartmentalized to reducethe risk of contamination between the stations 12, 14 and to permitlocalized abatement for contamination risks posed by specific station12, 14.

Contamination risks include, for example, vibration, heat, electrical,liquid, and other sources of contamination common to the includedcomponents and/or automated clinical instruments. Contamination may befurther reduced by including a ventilation system for each of the samplepreparation station 12 and the sample analysis station 14 so as tocontrol air flow through that station 12, 14 and to accommodate theanticipated heat generation by that station 12, 14. In similar manner,reagent storage areas, specimen storage areas, and sample storage areasmay include individual refrigeration systems to maintain those portionsat a lower relative temperature.

The housing 16 may be configured to have a front face 160 proximate tothe user and an opposing rear face 168 (FIG. 2A), a top surface 162positioned above a bottom surface 170 proximate to the floor, and aright-hand sidewall 164 and an opposing left-hand sidewall 166.References to terms such as “above,” “upper,” “below,” and “lower” arefor convenience of description only and represent only one possibleframe of reference for describing a particular embodiment. In thatregard, the system 10 is designed to include as many laboratory usertouch points at or near the front face of the housing 16 as possible.For example, as depicted in FIG. 1A, each of the LC columns 110, 112,specimen racks 28, reagent racks 38, a water and/or methanol supply 122,a washing solution supply 92, the waste containers 70 buffer and mobilephase containers 128, reaction vessel plates (not shown), and disposablepipette tip plates 66 (in a tip storage station 64) are positioned atthe front face of the housing 16 of the system 10 to allow easy accessfor replenishment and routine maintenance by the user. Similarly, thoseportions of the stations 12, 14 that do not require regular access bythe user are positioned within the system 10 space away from the frontface of the system 10. For example, LC pumps 124, power supplies 162,and controllers 21, 23 may be positioned within the housing 16 andspaced away from those components that are placed for easy access,generally referred to as “serviceable components.”

Also, those components that may require attention by a servicetechnician providing service to the system 10 are positioned to provideaccessible, if not optimally convenient, access. For example, the LCpumps 124, which may require access by the service technician, may bepositioned behind the waste containers 70 such that the serviceablecomponent waste containers 70 may be removed to service the LC pumps124.

Further, the laboratory user touch points are designed with a preferencefor the front face of the system 10, rather than the side of the system10, to reduce the system footprint in the laboratory environment; if thelaboratory user does not require regular access to the side of thesystem 10, the laboratory can pack other instruments closer to thesystem 10.

One of ordinary skill in the art will readily appreciate thatincorporation of the centrifuge 76 into an integral housing with theanalytical instrumentation of the system 10 may cause undesirableinterference with those analytical instruments. In this integralconfiguration example, the ability of the analytical instruments toperform with a particular reliability may be compromised. This may bedue to, at least in part, the high rotational speed required to drawdown the precipitating solids from the supernatant liquid. Therefore, itmay be necessary for embodiments of the system 10 including anintegrated centrifuge 76 to further include features that reducetransmission of vibrations thereof to other components of the system 10.Moreover, because of the desire to reduce the overall footprint of thesystem 10, the overall size of the centrifuge 76 may be reduced and/orconfigured to be a standalone centrifuge 76 that is not integral withother components of the system 10, but yet accessible by the transportassembly 50.

The mobile phase reagents 128 that feed the LC pumps 124 may bepositioned above the LC pumps 124. As depicted in FIGS. 3A and 3B, themobile phase reagents 128 are positioned in the upper right quadrant ofthe system 10. Positioning the mobile phases above the LC pumps 124 andvalves permits gravity to assist the feed of liquid mobile phasereagents 128, which results in easier priming of the LC tubing and thecreation of fewer bubbles in the LC lines as compared to placing themobile phase reagents 128 adjacent or below the LC pumps 124. Also, themobile phase reagents 128 may be positioned near the front face of theinstrument and at a height that falls approximately between theshoulders and waist of the average user.

According to one embodiment, the mass spectrometer 120 is positioned inthe lower portion of the instrument. Because the mass spectrometer 120is relatively heavy, placing the mass spectrometer 120 in a lowerposition improves the balance and stability of the overall system 10.More specifically, as depicted in FIGS. 3A-3B, the mass spectrometer 120is positioned in the lower right quadrant of the system 10.

The mass spectrometer 120 is positioned on a support that is moveablehorizontally with respect to the housing, for example, a sliding drawer,capable of moving the mass spectrometer into and out of the systemfootprint. Placing the mass spectrometer 120 on a drawer providesseveral benefits, including improved access to all sides of theinstrument for routine maintenance and servicing, improved manufacturingefficiency by permitting the mass spectrometer 120 to be installed ontothe drawer and then slidingly inserted into the housing 16, eliminatingthe step of inserting a bulky and heavy component within a restrictedspace inside the housing 16, and relative isolation of the sensitivemass spectrometer 120 from vibrational, thermal, electrical, liquid andother contamination emanating from other components of the system 10.

The serviceable components of the mass spectrometer 120 are positionedon the front face of the mass spectrometer 120 or on the top of the massspectrometer 120, rather than on or near the rear of the massspectrometer 120. Serviceable components include, but are not limitedto, the ionization source 140. However, due to its size and shape,placing the ionization source 140 on the front of the mass spectrometer120 creates a protrusion on the front of the system 10, extending beyondthe front plane of the housing 16. Therefore, the ionization source 140is designed to be removed during system transport and installed onto themass spectrometer 120 during installation of the system 10 within thelaboratory environment.

Due to the relative height of the mass spectrometer 120, and also due tothe relative height of the sample preparation station 12, it ispreferred that the mass spectrometer 120 is positioned in a quadrant ofthe system 10 opposite from the sample preparation station 12. Forexample, as depicted in FIG. 3A, the mass spectrometer 120 is positionedin the right quadrant and at a lower height as compared to the samplepreparation station 12, which is positioned in the left quadrant and ata higher height than the mass spectrometer 120 of the system 10;however, in FIG. 3B, both the mass spectrometer 120′ and the samplepreparation station 12′ are positioned in the left half of the system10′. Additionally, due to the possibility of vibrational and liquidcontamination emanating from the sample preparation station 12, whichcontamination may interfere with the operational precision of the massspectrometer 120, it is preferred that the sample preparation station 12is located not directly above the mass spectrometer 120.

Also in consideration for the relative height of the mass spectrometer120, and for the relative height of the LC pumps 124, it is preferredthat the LC pumps 124 are positioned not directly above the massspectrometer 120. However, the mass spectrometer 120 is preferablypositioned relatively close to the LC pumps 124, which LC pumps 124 arelocated in the central lower portion of the overall system 10, asdepicted in FIG. 3A-3B. Placing the LC pumps 124 relatively close to themass spectrometer 120 is important to minimize, as much as possible, thedistance of the fluidic connections between the LC pumps 124 and themass spectrometer 120, which thereby reduces the liquid dead volume inthe LC system lines and also reduces the risk of degradation of thechromatography caused by the separated liquid traveling over a distance.

While most of the system components are located within the housing 16,one or more components may optionally be located remotely from thesystem 10, either adjacent to the system 10 or at some distance from thesystem 10, but integrated into the system 10 using tubing or the like.For example, mechanical pumps, including roughing pumps, a nitrogengenerator or other inert gas sources for operation of the massspectrometer 120 may be located in a separate frame or frames. Due totheir thermal output, as well as their noise and vibration, placement ofthese components within the housing 16 is not advantageous. While thesecomponents could be integrated within the housing 16, they also can belocated remotely without denigrating system performance. Having theoption to locate these components remotely, for example, in anotherlocation within the same laboratory environment, or even in an adjacentroom within the overall laboratory, provides significant installationflexibility for the laboratory operator.

While the present invention has been illustrated by a description ofvarious embodiments, and while these embodiments have been described insome detail, they are not intended to restrict or in any way limit thescope of the appended claims to such detail. Additional advantages andmodifications will readily appear to those skilled in the art. Thevarious features of the invention may be used alone or in anycombination depending on the needs and preferences of the user. This hasbeen a description of the present invention, along with methods ofpracticing the present invention as currently known. However, theinvention itself should only be defined by the appended claims.

What is claimed is:
 1. A sample preparation and analysis system,comprising: a housing; a sample preparation station comprising acentrifuge positioned within the housing; a sample analysis stationcomprising a mass spectrometer positioned within the housing andinterconnected in an automated manner with the sample preparationstation; and a transport assembly configured to move at least one samplewithin the housing in an automated manner between the sample preparationstation and the sample analysis station, wherein the mass spectrometeris contained within a sliding drawer within the housing in the lowerportion of the system.
 2. The sample preparation and analysis system ofclaim 1, wherein the sample preparation station is positionedsubstantially on one side of the housing, at a height that is greaterthan a height of a base of an analyzer included in the sample analysisstation; and the analyzer is positioned substantially on the other sideof the housing, at a height that is less than a height of a base of thesample preparation station.
 3. The sample preparation and analysissystem of claim 1, wherein the sample analysis station further includesone or more liquid chromatography pumps and at least one liquidchromatography mobile phase container, the at least one liquidchromatography mobile phase container being positioned at a height thatis greater than a height of the one or more liquid chromatography pumps.4. The sample preparation and analysis system of claim 1, wherein thesample analysis station further includes an analyzer selected from thegroup consisting of a liquid chromatograph directly coupled to the massspectrometer, a gas chromatograph directly coupled to the massspectrometer, a surface desorption/ionizer directly coupled to the massspectrometer, a liquid chromatography ultra-violet spectrometer, and afluorescence spectrometer.
 5. The sample preparation and analysis systemof claim 1, wherein the sample preparation station includes at least oneof a specimen dock having one or more specimen racks capable of holdinga specimen container and a reagent station having one or more reagentracks capable of holding one or more reagent containers.
 6. The samplepreparation and analysis system of claim 1, further comprising a userinterface, wherein the user interface is located centrally along theoverall length of the housing between a left-hand sidewall of thehousing and a right-hand sidewall of the housing.
 7. The samplepreparation and analysis system of claim 1, wherein the transportassembly is configured to move the sample in at least one of an x-ydirection, an x-y-z direction, or a rotary direction.
 8. The samplepreparation and analysis system of claim 1, wherein the transportassembly includes a sample pipette assembly.
 9. The sample preparationand analysis system of claim 1 further comprising a secondary processingstation that includes one or more of a mixing station, an incubationstation, and a matrix interference removal station and wherein thetransport assembly is configured to move the at least one sample betweenthe sample preparation station, the secondary processing station, andthe sample analysis station.
 10. The sample preparation and analysissystem of claim 1 further comprising an injector station positioned inthe housing, wherein the injection station is configured to receive asample prepared from the transport assembly and transfer an aliquot ofthe sample to the sample analysis station.
 11. A sample preparation andanalysis system, comprising: a housing; a sample preparation stationpositioned within the housing and configured to prepare a sample takenfrom a specimen in accordance with an assay selected from a databasecontaining a plurality of unique assays; a sample analysis stationpositioned within the housing and spaced away from the samplepreparation station, the sample analysis station comprising an analyzercomprising a mass spectrometer, the analyzer being dynamicallyreconfigurable in response to the selected assay to analyze the preparedsample in accordance with the selected assay; and a transport mechanismincluding a rotatable table configured to transport a vial containingthe prepared sample within the housing and from the sample preparationstation to the sample analysis station.
 12. The sample preparation andanalysis system of claim 11, wherein the sample preparation station ispositioned substantially on one side of the housing, at a height that isgreater than a height of a base of an analyzer included in the sampleanalysis station; and the analyzer is positioned substantially on theother side of the housing, at a height that is less than a height of abase of the sample preparation station.
 13. The sample preparation andanalysis system of claim 11, wherein the sample analysis station furtherincludes one or more liquid chromatography pumps and at least one liquidchromatography mobile phase container, the at least one liquidchromatography mobile phase container being positioned at a height thatis greater than a height of the one or more liquid chromatography pumps.14. The sample preparation and analysis system of claim 11, wherein thesample preparation station includes at least one of a specimen dockhaving one or more specimen racks capable of holding a specimencontainer and a reagent station having one or more reagent racks capableof holding one or more reagent containers.
 15. The sample preparationand analysis system of claim 11 further comprising a user interface,wherein the user interface is located centrally along the overall lengthof the housing between a left-hand sidewall of the housing and aright-hand sidewall of the housing.
 16. The sample preparation andanalysis system of claim 11, wherein the sample analysis station furtherincludes an analyzer selected from the group consisting of a liquidchromatograph directly coupled to the mass spectrometer, a gaschromatograph directly coupled to the mass spectrometer, a surfacedesorption/ionizer directly coupled to the mass spectrometer, a liquidchromatography ultra-violet spectrometer, a fluorescence spectrometer,and combinations thereof.
 17. The sample preparation and analysis systemof claim 11, wherein the transport mechanism further includes at leastone of a transport assembly, an injector pipette assembly, a fluidiccoupler, or combinations thereof.
 18. The sample preparation andanalysis system of claim 17, wherein the transport assembly isconfigured to move the sample in at least one of an x-y direction, anx-y-z direction, or a rotary direction.
 19. The sample preparation andanalysis system of claim 11, further comprising a secondary processingstation that includes one or more of a mixing station, an incubationstation, and a matrix interference removal station and wherein thetransport mechanism is configured to transport the prepared samplewithin the housing and from the sample preparation station to the sampleanalysis station, from the sample preparation station to the secondaryprocessing station and from the secondary processing station to thesample analysis station.
 20. An automated biological specimenpreparation and mass spectrometry analysis system for analyzing aplurality of biological specimens, comprising: a sample preparationstation configured to prepare samples taken from the plurality ofbiological specimens; a secondary processing station configured toreceive samples from the sample preparation station and including one ormore of a mixing station, an incubation station, and a matrixinterference removal station; and a sample analysis station including amass spectrometer configured to receive samples from the secondaryprocessing station and to quantify one or more analytes in one or moreof the processed samples; wherein the sample preparation station and thesample analysis station are contained within a housing and such that themass spectrometer is positioned at a height that is lower than a heightof the sample preparation station; wherein the mass spectrometer iscontained within a sliding drawer within the housing.